Warren, K. et al. Phase II trial of intravenous lobradimil and carboplatin in childhood brain tumors: a report from the Children's Oncology Group. Cancer Chemother. Pharmacol. 58, 343-347

National Cancer Institute/Neuro-Oncology Branch, Bethesda, MD 20892-8200, USA.
Cancer Chemotherapy and Pharmacology (Impact Factor: 2.77). 09/2006; 58(3):343-7. DOI: 10.1007/s00280-005-0172-7
Source: PubMed


[corrected] Lobradimil is a synthetic bradykinin analog that rapidly and transiently increases the permeability of the blood-brain barrier (BBB). The combination of lobradimil and carboplatin was studied in pediatric patients with primary brain tumors in a phase II trial, the primary endpoints of which were to estimate the response rate and time to disease progression.
Patients were stratified by histology into five cohorts: brainstem glioma, high-grade glioma, low-grade glioma, medullobastoma/primitive neuroectodermal tumor (PNET), and ependymoma. Patients received carboplatin adaptively dosed to achieve a target AUC of 3.5 mg min/ml per day (7 mg.min/ml/cycle) intravenously over 15 min on 2 consecutive days and lobradimil 600 ng/kg ideal body weight/day on 2 consecutive days each 28 day cycle.
Forty-one patients, age 2-19 years, were enrolled; 38 patients, including 1 patient ultimately determined to have atypical neurocytoma, were evaluable for response. No objective responses were observed in the brainstem glioma (n=12) and high-grade glioma (n = 9) cohorts, although two patients with high-grade glioma had prolonged disease stabilization (>6 months). The study was closed for commercial reasons prior to achieving the accrual goals for the ependymoma (n = 8), medulloblastoma/PNET (n = 6) and low-grade glioma (n = 2) cohorts, although responses were observed in 1 patient with PNET and 2 patients with ependymoma.
The combination of lobradimil and carboplatin was inactive in childhood high-grade gliomas and brainstem gliomas.

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    • "Delivery Method Description Most Recent Clinical Trial Chemical-mediated BBB dis- ruption Transient inflammatory response in endothelial lining, investigated w/ LTC4, alkylglycerols, IL-2, RMP-7, bradykinin, & TNF-a/IFN-g Warren et al., 2001 & 2006; Grant et al., 2002 "
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    ABSTRACT: Object: Fluorescein, a dye that is widely used as a fluorescent tracer, accumulates in cerebral areas where the blood-brain barrier is damaged. This quality makes it an ideal dye for the intraoperative visualization of high-grade gliomas (HGGs). The authors report their experience with a new fluorescein-guided technique for the resection of HGGs using a dedicated filter on the surgical microscope. Methods: The authors initiated a prospective Phase II trial (FLUOGLIO) in September 2011 with the objective of evaluating the safety of fluorescein-guided surgery for HGGs and obtaining preliminary evidence regarding its efficacy for this purpose. To be eligible for participation in the study, a patient had to have suspected HGG amenable to complete resection of the contrast-enhancing area. The present report is based on the analysis of the short- and long-term results in 20 consecutive patients with HGGs (age range 45-74 years), enrolled in the study since September 2011. In all cases fluorescein (5-10 mg/kg) was injected intravenously after intubation. Tumor resection was performed with microsurgical technique and fluorescence visualization by means of BLUE 400 or YELLOW 560 filters on a Pentero microscope. Results: The median preoperative tumor volume was 30.3 cm(3) (range 2.4-87.8 cm(3)). There were no adverse reactions related to fluorescein administration. Complete removal of contrast-enhanced tumor was achieved in 80% of the patients. The median duration of follow-up was 10 months. The 6-months progression-free survival rate was 71.4% and the median survival was 11 months. Conclusions: Analysis of these 20 cases suggested that fluorescein-guided technique with a dedicated filter on the surgical microscope is safe and allows a high rate of complete resection of contrast-enhanced tumor as determined on early postoperative MRI. Clinical trial registration no.: 2011-002527-18 (EudraCT).
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    • "Several strategies have been employed to overcome the BBB and improve drug delivery to the tumor site. These include the use of high dose chemotherapy with stem cell rescue (Finlay and Zacharoulis, 2005), biologic or osmotic BBB disruption (Hall et al., 2006; Warren et al., 2006), and p-glycoprotein inhibition (Greenberg et al., 2005). Most recently, convection-enhanced delivery has been used to deliver agents directly into the tumor of patients with DIPG (Lonser et al., 2007). "
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    Frontiers in Oncology 12/2012; 2:205. DOI:10.3389/fonc.2012.00205
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    • "Osmotic BBB opening has already been successfully used to increase the effectiveness of chemotherapy in animals and humans with central nervous system tumors [7]. Other methods to overcome the BBB with therapeutic intention are the use of new lipophilic chemotherapeutic agents [8], drug administration as liposomal-coated nanoparticles [9], BBB opening with bradykinin B2 receptor agonists like cereport (RMP-7, Lobradimil) [10, 11], or the co-administration of P-glycoprotein blocking drugs [12]. "
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